Certain bis-(alkylaminomethyl)-pyridines



United. States Patent cc CERTAIN BIS-(ALKYLAMINOMETHYL)- PYRIDINES Renat Herbert Mizzoni, Chester, NJ., assignor to Ciba Pharmaceutical Products, Inc., Summit, N.J., a corporation of New Jersey No Drawing. Filed Apr. 23, 1958, Ser. No. 730,261

4 Claims. (Cl. 260-296) The present invention relates to pyridine derivatives. More particularly, it concerns pyridine derivatives of the formula: W

in which each of the radicals R and R represents an aliphatic hydrocarbon radical, containing from 1 to 12 carbon atoms, and salts thereof, as well as process for the preparation of such compounds. Aliphatichydrocarbon radicals are particularly alkyl radicals having frorn'l to 8 carbon atoms, such as unlpranched alkyl radicals, e.g. methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl; branched alkyl radicals, e.g. l-methyl-pentyl or isoctyl. Also anticipated are alkenyl radicals, containing from 4 to 12 carbon atoms, e.g. 7-octenyl or 9-decenyl.

The pyridine ring is preferably unsubstituted or may contain as additional substituents lower alkyl groups, e.g. methyl or ethyl.

Salts of the new pyridine compounds of this invention are particularly therapeutically useful acid addition salts, for example, those with inorganic acids, such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; thiocyanic acid; sulfuric or phosphoric acids; or those with organic acids, such as formic, acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, ascorbic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, mandelic, salicylic, 4-aminosalicylic, Z-phenoxybenzoic, 2-acetoxy-benzoic, methane sulfonic, ethane sulfonic, hydroxyethane sulfonic, benzene sulfonic, p-toluene sulfonic, naphthalene sulfonic or sulfanilic acid or methionine, tryptophane, lysine or arginine.

The new pyridine derivatives of this invention are active against Mycobacteria, especially Mycobacterium tuberculosis and may therefore be used as tuberculostatic agents. Especially valuable with respect to their tuberculostatic activity are the compounds of the formula:

in which each of the radicals R and R stands for alkyl radicals containing from 4 to 12 carbon atoms, particularly for identical alkyl radicals, and the therapeutically active acid addition salts thereof. Preferred are those compounds in which the alkyl radicals R and R have 4 to 8 carbon atoms; especially preferred is the compound in which R and R are each n-octyl. These compounds are active in low concentrations against the human patho- 'genic strain H 37 Rv of Mycobacterium tuberculosis.

Patented Dec. 6, 1960 2 Representing this group is the pyridine compound of the formula:

v ceutical preparations may be in solid form, for example,

as tablets, dragees or capsules or in liquid form, for example, as solutions, suspensions or emulsions. If desired, they may contain auxiliary substances, such as preserving agents, stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They may also contain, in combination, other therapeutically useful substances.

Althoughseveral methods for the preparation of the compounds of this invention may be devised, I prefer to preparethe new pyridine compounds by reducing in a compound of the formula:

in which R and R have the above-given meaning, or salts thereof, thetwo Schiif base-type double bonds, and, if desired, converting a resulting salt to a base, and/or, if desired, converting a base to a salt thereof.

The reduction of the Schiif base-type double bond may be car-tied out by using catalytically activated hydrogen or a di-light metal hydride as hydrogenating agents. Catalysts containing a metal of the eighth group of the periodic system may be used in the presence of hydrogen; for example, palladium, e.g. palladium on charcoal is a suitable metal catalyst. The reduction is carried out by treating a solution, for example, an alcohol, e.g. methanol or ethanol, solution of the Schiir' base with hydrogen, if desired, at an increased pressure, in the presence of the catalyst. In choosing a catalytic hydrogenation process, care has to be taken to avoid a hydrogenation of the pyridine ring.

. The preferred reduction reagents are di-light metal hydrides, such as alkali metal borohydrides, e.g. lithium borohydride, or sodium borohydride; alkali metal aluminum'hydrides, e.g. lithium aluminum hydride or sodium aluminum hydride, or alkaline earth metal aluminum hydrides, e.g. magnesium aluminum hydride. The reduction with these reagents is preferably carried in solution, the solvents being chosen according to the reactivity of the reagent. For example, an alcohol, such as a lower alkanol, e.g. methanol, ethanol or isopropanol, if desired, aqueous mixtures thereof, may be used with alkali metal borohydrides, or an ether, e.g. diethylether, tetrahydrofurane or 1,4-dioxane, with alkali metal aluminum hydrides. If desired, the reaction may be promoted by the addition of catalytic amounts of an activator, for example, of aluminum chloride. The reaction is performed at 00m temperature of preferably at an elevated temper'ature, for exa'mple,at the boiling temperature of the in which R and R have the above-given meaning, as well as the salts thereof, are new and are intended to be included in the scope of this application. They may be prepared according to the general procedures known for the preparation of Schiff bases, for example, by reacting a pyridine-di-carboxa1dehyde with an amine, if desired, in the presence of a solvent, such as an alcohol, for example, a lower alkanol, e.g. methanol or ethanol, and/ or under cooling, at room temperature or at an elevated temperature.

The compounds of this invention, i.e. the final products and the intermediate Schiff bases, are isolated and purified according to the usual methods, for example, by extraction, crystallization, recrystallization, absorption, elution, etc.

The above described process is particularly suitable for those pyridine compounds in which R and R stand for the same aliphatic hydrocarbon radical. However, compounds in which R and R represent different radicals, may be obtained.

Depending on the conditions used the new compounds of this invention may be obtained in the form of the free bases or as the salts thereof. A salt may be 'con verted into the free base in the customary way, for example, by reaction with an aqueous alkaline reagent, such as an alkali metal hydroxide, e.g. sodium or potassium hydroxide, an alkali metal carbonate, e.g. sodium carbonate or potassium hydrogen carbonate, or ammonia. A free base may be transformed into its therapeutically useful acid addition salts by reaction with appropriate inorganic or organic acids, such as those outlined hereinabove, if desired, in an alcohol, e.g. methanol, ethanol, propanol or isopropanol, solution or in an ether, e.g. diethylether, solution or in a mixture of such solvents. If acids of gaseous nature, such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, are used, the base may be dissolved in a hydrocarbon solvent, e.g. petroleum ether, pentane or hexane, and the gaseous hydrogen halide is passed through the solution, whereupon the salt may precipitate.

The following examples illustrate the invention; they are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example I A solution of 6.7 gm. of pyridine-2,G-di-carboxaldehyde in 100 ml. methanol is added with swirling to a solution of 7.3 g. n-butylamine in 100 ml. methanol. The resulting mixture is allowed to stand for /2 hour, and 1 ml. of 4 N-sodium hydroxide is added, then 7 g. of sodium borohydride is added portionwise over a /2 hour period. After standing for 24 hours the solvent .is removed from the reaction mixture and the residue is suspended in water. An excess of cone. aqueous sodium hydroxide is added and the supernatant oil is extracted into ether. The dried ether extract is thoroughly heated with anhydrous hydrogen chloride. The resulting solid is recrystallized from isopropanol-ethyl acetate to yield the desired 2,6-bis-(n-butylaminomethyl)-pyridine dihydrochloride, M.P. 181.5-1835.

Example 2 The procedure of Example 1 is followed except that 10.1 g. n-hexylamine is substituted for the 7.3 g. n-butylamine of the reference example to yield the desired 2,6-

4 bis (n hexylaminomethyl) pyridine M.P. 208.-209.5 C.

dihydrochloride,

Example 3 To a solution of 20 g. of 2,6-bis-(n-octyliminomethylene)-pyridine in 250 ml. of methanol is added over a period of one hour and in portions a total of 5 g. of sodium borohydride. The solvent is removed by distillation, the residue is suspended in water and an excess of a concentrated aqueous solution of sodium hydroxide is added. After extracting with ether and drying the ether solution over magnesium sulfate, the solution is treated with gaseous hydrogen chloride to yield 18.8 g. of the 2,6-bis-(noctylaminomethyl)-pyridine dihydrochloride is collected, which is recrystallized from isopropanol, M.P. 209-212.

Instead of using sodium borohydride as the reducing agent the methanol solution of the Schiff base may be treated with hydrogen in the presence of palladium on charcoal to form the desired 2,6-bis-(n-octylaminomethyl)-pyridine, which is characterized as the dihydrochloride.

The starting material may be prepared as follows: 25.86 g. of n-octylamine is added to a solution of 13.5 g. of pyridine-2,-dicarboxaldehyde in 250 ml. of methanol. The precipitated 2,6-bis-(n-octyliminomethylene)- pyridine is filtered off and dried, M.P. 37.5-38.5 yield: 26 g.

Example 4 A solution of 35.3 g. of 2,6-bis-(2,2,4,4-tetramethylbutyliminomethylene)-pyridine in methanol is treated with 5 g. of sodium borohydride according to the procedure described in Example 3; 15.6 g. of 2,6-(2,2,4,4- tetramethylbutylaminomethyl) -pyridine dihydrochloride is obtained and recrystallized from isopropanol, M.P. 2l7-221.

The starting material may be prepared according to the method given in Example 3; the 2,6-bis-(2,2,4,4-tetramethylbutylirninomethylene)-pyridine is an oily substance and is used without further purification.

Example 5 A solution of 20 g. of 2,6-bis-(n-decyliminomethylene)-pyridine in 300 ml. of methanol is treated with 5 g, of sodium borohydride as described in Example 3; the 2,6-bis-(n-decylaminomethyl) pyridine dihydrochloride melts at 2l4.5-2l5.5 after recrystallization from isopropanol; yield: 16.2 g.

The starting material may be prepared as described in Example 3; the 2,6-bis-(n-decyliminomethylene) pyridine melts at 54.5-55.5.

Example 6 By reacting 2,4-bis-(n-dodecyliminomethylene)-pyridine with sodium borohydride according to the procedure given in Example 3 the 2,4-bis-(n-dodecylaminomethyl)- pyridine hydrochloride may be obtained.

The starting material used in the above reaction may be obtained by reacting pyridine-2,4-dicarboxaldehyde with n-dodecylamine according to the procedure given in Example 3; the reaction product is used without further purification.

The new pyridine compounds may also be prepared according to the following procedures: An amide of the formula:

\N CO-NHR: in which R and R have the above-given meaning, may be converted to the desired amine by using a reagent capable of reducing the carbonyl portion of theamide grouping to a methylene group, and, if desired, the optional steps may be carried out. Reducing agents which may be used in the above reaction are especially alkali metal and alkaline earth metal aluminum hydrides, e.g.

5 sodium aluminum hydride, magnesium aluminum hydride and, particularly, lithium aluminum hydride, which reagents may also be used in the presence of an activator, for example, aluminum chloride. The reaction is carried out in the presence of a solvent, for example, an ether solvent, e.g. diethylether, tetrahydrofurane or 1,4- dioxane, and, if desired, at an elevated temperature, for example at the boiling temperature of the solvent. The amines may also be obtained by electrolytically reducing the amides on a cathode of high overpotential such as a cadmium, zinc, mercury, lead amalgam or lead. The catholyte used in such a reduction is preferably a mixture of water, sulfuric acid and an alkanoic acid, e.g. acetic acid. A platinum, carbon, lead or stainless steel anode may be used; the anolyte is preferably sulfuric acid.

A modification of this process comprises treating a pyridine compound of the formula:

\N CHp -NH-C o-R. in which each of the radicals R and R represents an aliphatic hydrocarbon radical which contains one carbon less than the radicals R and R respectively, with the above-mentioned reducing reagents capable of converting the carbonyl group of an amide grouping into a methylene group, and, if desired, carrying out the optional steps.

The starting materials used in the above reactions may be prepared according to procedures generally used for the preparation of acid amides, for example, treatment of an acid halide, e.g. chloride, with an amine.

Instead of using the amide derivatives the corresponding thioamides may be used for the preparation of the compounds of this invention. The replacement of the sulfur in such thioamides may, for example, be carried out by treatment with freshly prepared Raney nickel in an alcoholic solvent, e.g. methanol or ethanol; or electroly'tically according to the procedure outlined hereinabove for the reduction of the amides.

The new pyridine derivatives of this invention may also be prepared by reacting a pyridine compound of the formula:

in which X stands for a reactive esterified hydroxyl group, or a salt thereof with an aliphatic hydrocarbon amine containing from 4 to 12 carbon atoms, or by treating a pyridine compound of the formula:

CHzX

HINHiC HINH:

such as a mineral acid, for example, a hydrohalic acid,

e.g. hydrochloric, hydrobromic or hydriodic acid, or sulfuric acid, or a strong organic acid, such as an aryl sulfonic acid, e.g. p-toluene sulfonic acid, or a lower alkyl sulfonic acid, e.g. methane sulfonic acid or ethane sulfonic acid. The radical X is primarily represented by a halogen atom having an atomic weight greater than 19, such as chlorine, bromine or iodine. The reaction is preferably carried out by treating the amine with the aliphatic hydrocarbon reagent in such a way that an excess of the amine is always present, thus avoiding the formation of tertiary amines. Alcohols, such as methanol or ethanol, e.g. 95% ethanol, are the preferred solvents, and alkali metal carbonates, e.g. sodium carbonate or potassium hydrogen carbonate, or organic bases, e.g. pyridine are used to neutralize the generated acid.

The starting materials used in the above reaction are known or may be prepared according to methods used for the preparation of the known compounds.

In each of the above mentioned processes, the reactions may not have to be carried out in such a manner that both of the pyridine nucleus are introduced simultaneously; each of the substituents may be introduced individually, or, any additional carbon-carbon double bond in one or both of the aliphatic hydrocarbon radicals may be reduced simultaneously or subsequently with either the carbon-nitrogen double bond of the Schiff base or the carbon-oxygen double bond of an amide, or subsequently to the reaction of an amine with a reactive ester of a hydroxylated compound. Therefore, the invention also comprises any modification of the general process, wherein a compound obtainable as an intermediate at any stage of the process issued as starting material and the remaining step(s) of the process is(are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

What is claimed is:

1. 2,6-bis (n-octylaminomethyl)-pyridine.

2. 2,6-bis-(2,2,4,4-tetramethylbutylaminomethyl) pyridine.

3. 2,6-bis-(n-decylaminomethyl)-pyridine.

4. 2,4bis-(n-dodecylaminomethy1)-py1idine.

References Cited in the file of this patent UNITED STATES PATENTS 2,349,318 Westphal May 23, 1944 FOREIGN PATENTS 670,991 Great Britain Apr. 30, 1952 OTHER REFERENCES Graf et al.: Chem. Abstracts, vol. 30, col. 7576 (1936).

Michalski et al.: Chem Abstracts, vol. 50, col. 12044 (1956).

Gaylord: Reduction With Complex Metal Hydrides (Interscience), pp. 795-796; 806 (1956).

Sauermilch et al.: Chem. Abstracts, vol. 49, col. 7567 (1955). 

1. 2,6-BUS-(N-OCTYLAMINOMETHYL)-PYRIDINE.
 2. 2,6-BIS-(2,2,4,4-TETRAMETHYLBUTYLAMINOMETHYL - PYRIDINE.
 3. 2,6-BIS-(N-DECYLAMINOMETHYL)-PYRIDINE.
 4. 2,4-BIS-(N-DODECYLAMINOMETHYL)-PYRIDINE. 